Neisseria gonorrhoeae, the etiologic agent of gonorrhea, exhibits tremendous levels of variation during the course of disease. The mechanisms for antigenic and phase variation are under intense study to determine the biological importance of these phenomena in the pathogenesis of neisserial infections. We have studied one family of outer-membrane proteins (the Opa or ~opacity-related~ proteins) which have been shown to be expressed in vivo during natural and human challenge infections. We have focused on the genetic mechanisms used by the organism to vary expression of this protein family and the biological properties associated with expression. The expression state changes ("phase variation") of the opa multigene family are controlled by an unusual form of gene regulation, which serves as a paradigm for other genes and gene families which utilize similar means of genetic variation. Changes in the number of short DNA repeats within the coding region of the individual genes alters their ability to be fully translated into mature proteins ("translational-frameshifting"). We have identified a number of cellular processes which influence the ability of the bacterium to control the rate of change in these repetitive sequences. The rate of transcription of variable genes is proportional to the rate of phase variation, an important potential regulatory process. A number of gene products have been shown to play a role in the DNA rearrangements responsible for phase variation. We have isolated a number of these genes from N. gonorrhoeae and are analyzing their role in phase variation. Opa proteins have previously been described as imparting a wide variety of biological phenotypes (generally involving increased adherence to human cells). We have focused our studies on the role of Opa protein expression in resistance to early (i.e. non-immune) host defense mechanisms. Specifically, the influence of Opa protein expression on the ability of bacterial cells to resist killing by human complement (in normal human serum, NHS) and the adherence to human PMNs (in the presence and absence of NHS).